Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by autonomic and motor dysfunction with widespread CNS demyelination. ADLD is unique among leukodystrophies with an exclusively late age of onset, suggesting that mechanisms specifically involving age- dependent myelin regulation are affected. We have previously shown that ADLD is caused by duplications of the LMNB1 gene, which encodes lamin B1, and that increased expression of lamin B1 underlies the disease process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent to the inner nuclear membrane. The nuclear lamina maintains the structural integrity of the nucleus and has roles in essential cellular processes including transcription, DNA replication, DNA repair, and epigenetic regulation. Abnormalities in the nuclear lamina have been shown to be involved in both normal and pathological aging. The mechanisms linking increased lamin B1 over-expression to age-dependent demyelination in ADLD are unknown. To address these questions, I have generated transgenic (TG) mouse models with LMNB1 over-expression targeted to specific cell types in the CNS. TG-LMNB1 mice with lamin B1 over-expression targeted to oligodendrocytes (the cell types that produce myelin in the CNS) show striking age-dependent motor dysfunction, muscle weakness and paralysis reminiscent of symptoms seen in ADLD patients. Specific Aim 1 will elucidate pathophysiological pathways that underlie ADLD, using phenotypic and histo- pathological assays of age-dependent neurodegeneration in TG-LMNB1 mice. Motor function in TG-LMNB1 mice will be assessed at different ages to determine the earliest onset of symptoms and the temporal progression of the degenerative phenotype. Histo-pathological analysis of the brain and spinal cord will allow us to determine the structures involved and the nature of the degenerative process and how it evolves over time. Specific Aim 2 will test the hypothesis that age-dependent dysregulation of lamin B1-controlled gene expression and chromatin modification in the oligodendrocyte underlies molecular pathways for ADLD. For this, we will perform genome-wide analyses of RNA expression and lamin B1-chromatin interactions in CNS from TG-LMNB1 vs. wild-type mice. This project will identify mechanistic links between age-dependent neurodegeneration in ADLD and the nuclear lamina. In the future, TG-LMNB1 mice can be used to develop therapeutic approaches for ADLD. An understanding of the basis of ADLD may provide insight into demyelination in common diseases (Multiple Sclerosis) and into cellular processes that link the nuclear lamina and aging.

Public Health Relevance

An increase in the amount of a protein called lamin B1 in the nervous system occurs in a disease known as Autosomal Dominant Leukodystrophy (ADLD), which leads to degeneration of the nervous system resulting in muscle wasting and weakness, difficulty with movements, paralysis, and early death. Having recently generated a mouse model for ADLD which also has increased lamin B1 levels in the nervous system and similar adult-onset clinical features, in this project, we will characterize the changes in gene regulation and pathology that occur in and lead to loss of the nervous system. This study will not only allow us to understand what causes the ADLD disease, but will provide a basis for future studies to develop potential therapies in ADLD as well as to better understand and treat similar common diseases such as Multiple Sclerosis. .